Antithrombotic properties of JJ1, a potent and novel thrombin inhibitor

Abstract

The development of new anticoagulants is an important goal for the improvement of thrombosis treatment. Recent studies have suggested the importance of thrombin inhibitors in the modulation of thromboembolic disorders. The aim of this study was to discover a new small-molecule thrombin inhibitor. In this study, the compound JJ1, which has a novel scaffold, was selected by structure-based docking simulation to determine its potential inhibitory activity against thrombin. JJ1 was shown to inhibit the catalytic activity of human α-thrombin with a K i of 0.019 μM by direct binding to the active site and with at least 10,000-fold selectivity relative to that reported for the inhibition of other biologically important serine proteases. JJ1 prolonged clotting times (activated partial thromboplastin time and prothrombin time) and inhibited the activity and production of thrombin. Furthermore, it inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Similar to its in vitro antithrombotic activities, JJ1 showed enhanced antithrombotic effects in an in vivo pulmonary embolism and arterial thrombosis model. It also exhibited anticoagulant effects in mice. Collectively, these results demonstrated that JJ1 was a potent, direct, and selective thrombin inhibitor that may be useful in the management of various thrombotic disorders.

Synthesis and anti-hepatocellular carcinoma activity of aminopyridinol–sorafenib hybrids

“…Intermolecular interactions were compared and visualised using the Grapheme Toolkit of Openeye package. The protocols in the previous study were employed for MMPBSA approach 50 . In brief, the SQM and LEaP programs in AMBER 18 generated the GAFF force fields of small molecules for the molecular dynamics (MD) simulation, whereas the ff14SB force field was employed for B-Raf (A chain of PDB code, 1UWJ).…”

Chemical Probes for Profiling of MALT1 Protease Activity

“…MALT1 is relevant in RA as it is involved in monocyte differentiation. [37] More specifically, allosteric inhibition of MALT1 blocks osteoclast formation and alleviates diseasesrelated symptoms in a mouse model of collagen-induced arthritis. [37][38]…”

Rodent models of pulmonary embolism and chronic thromboembolic pulmonary hypertension

“… FeCl 3 concentration– 1,8%. Exposure time – 5 min Studying of generation rate, stability and embolization risk in case of factor V Leiden (FVL) variant Femoral vein 2 h – [ 31 ] 6 Mice Collagen + epinephrine Collagen – 280 μg/kg; Epinephrine – 29 μg/kg Studying of inhibitor tyrosineproteinkinase MER effectiveness in platelets inactivation and blood clots prevention Intravenous (n/d) 15 min – [ 104 ] 7 Mice 1) Thromboplastin 2) Collagen + epinephrine Thromboplastin – 5 μL; Collagen – 64 μg/kg; Epinephrine – 5,4 μg/kg Studying of platelets TLT-1 receptor role of immune origin hemorrhage Intravenous (n/d) 30 min – [ 105 ] 8 Mice Collagen/2MeSADP + epinephrine Collagen – 400 μg/kg; 2MeSADP – 20 μg/kg; Epinephrine – 30 μg/kg Studying of platelets activation mechanisms in case of hemostasis retro-orbital sinus/Inferior vena cava Acute study (After respiratory distress) – [ 106 ] 9 Mice Collagen + epinephrine Collagen – 430 μg/kg; Epinephrine – 20 μg/kg Studying of glucose metabolism effect on platelets function regulation Intravenous (n/d) 25 min – [ 14 ] 10 Mice Collagen + epinephrine Collagen – 500 μg/kg; Epinephrine – 50 μg/kg Studying of thrombin inhibitor anticoagulant potency in PE prevention Tail vein 15 min – [ 107 ] 11 Mice Thromboplastin 7,5 μL/g Studying of the vaccination anticoagulant properties to factor XI in thrombosis prevention Intravenous (n/d) 3 min – [ 8 ] …”